With over 20 years into the AIDS pandemic, approximately 40 million people globally are estimated to be infected with human immunodeficiency virus (HIV). AIDS has claimed more than 22 million lives. Three million deaths occurred in 2001 alone. Despite the knowledge gained over the past two decades as to the molecular biology, pathogenesis and epidemiology of HIV, development of an effective HIV vaccine still continues to be an unprecedented challenge. Conventional strategies that have been successfully exploited in the past in developing effective vaccines against other human pathogens have proven ineffective in the case of HIV.
Despite the lack of definitive immune correlates that confer protection in humans, evidence from recent animal model experiments have suggested that vaccine-induced immunity to HIV is possible (Amara, et al., Science 292: 69-74, 2001; Rose, et al., Cell 106: 539-49, 2001; Barouch, et al., Science 290: 486-92, 2000; Shiver, et al., Nature 415: 331-5, 2000; Chen, et al., Nat. Med. 7: 1225-31, 2001). Studies in rhesus macaques with pathogenic chimeric SIV-HIV-1 (SHIV) have revealed that antibodies may play an important role in protection against HIV. For example, passively infused antibodies have been shown to prevent SHIV infection, not only in oral or vaginal challenge, but even when the SHIV challenge was provided intravenously (see, e.g., Shibata, et al., Nat. Med. 5: 204-10, 1999; Mascola, et al., Nat. Med. 6: 207-10, 2000). Cell-mediated immune mechanisms are also likely to play a dominant role in curtailing viral replication as well. This contention is well supported by many studies of SIV in nonhuman primates and studies in humans where cytotoxic T lymphocytes (CTLs) have been shown to be pivotal in controlling viral replication in both acute and chronic phases of the disease (Walker, et al., Nat. Med. 6: 1094-5, 2000).
As yet, no vaccine has been effective in conferring protection against IV infection. More significantly, current candidate vaccines do not induce efficient cellular responses against the infected cells, and therefore do not confer long term protection.
While peptide or polypeptide vaccines have been used successfully for certain pathologies, obstacles to using these vaccines to generate protective immune responses against HIV include the low immunogenicity of HIV peptides, the genetic variability of HIV, and the dependence of T cell epitopes on the patient's immunogenetic background.
Because of the low immunogenicity of peptides in general, they are typically administered with adjuvants to stimulate immune responses. Incomplete Freund's adjuvant and other oil-based adjuvants appear to be more effective and favor the induction of Th1 responses, while alum results in a preferentially Th2 response (Grun and Maurer, Cell Immunol. 121(1): 134-45, 1989). Additional adjuvant approaches to enhance the response to peptides include the covalent association with lipopeptidic immunostimulants, or the encapsidation of peptides into liposomes (Kim, et al., Int J Oncol. 21(5): 973-9, 2002; Martinon, et al., J Immunol. 149(10): 3416-22, 1992). Certain cytokines also have been demonstrated to be useful. In experiments in mice, IL-12 and the active fragment of IL-1β have been shown to enhance Th1 responses to peptides. IL-2 has been approved by the FDA for use in the treatment of patients with metastatic renal cell carcinoma or with metastatic melanoma (Antonia, et al., J Urol. 167(5): 1995-2000, 2002). It has been used as a component of vaccines for cancer and as an element of vaccine approaches in models of ADS (see, http://www.actis.org/vaccinetrials.asp). However, IL-2 administration is associated with the capillary leak syndrome and due to its role in activation-induced cell death (AICD), IL-2 may lead to death of T-cells that recognize the antigens expressed on the tumor cells. See, e.g., Waldmann, et al., Immunity 14: 105-10, 2001. Furthermore, the IL-2 inhibits the survival of memory CD8+ T-cells, potentially reducing its utility as an adjuvant in HIV vaccines.